Pharmacokinetic Drug Interaction Between Ezetimibe and Tacrolimus After Single Dose Administration in Healthy Subjects

Condition(s) targeted: Pharmacokinetics; Drug Interactions; Hypercholesterolemia; Immunosuppression

Intervention: 1 tablet Ezetrol(R) (ezetimibe), MSD Sharp & Dohme GmbH, Germany (Drug); 1 capsule Prograf(R) (tacrolimus), Astellas Pharma GmbH, Germany (Drug); 1 tablet Ezetrol(R) + 1 capsules Prograf(R) (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Ernst Moritz Arndt University of Greifswald

Official(s) and/or principal investigator(s):
Werner Siegmund, Prof, Principal Investigator, Affiliation: Department of Clinical Pharmacology

The purpose of this study is to confirm a significant influence of ezetimibe and tacrolimus on each others pharmacokinetics

Official title: Pharmacokinetic Drug Interaction Between Ezetimibe and Tacrolimus After Single Dose Administration in Healthy Subjects

Study design: Basic Science, Randomized, Open Label, Active Control, Crossover Assignment, Pharmacokinetics Study

Primary outcome: Primary characteristics: for ezetimibe: AUC0-∞, Cmax; for tacrolimus: AUC0-∞, Cmax

Secondary outcome: Second. characteristics: for ezetimibe: CLR, Ae (urine), Ae (feces); for ezetimibe glucuronide: AUC0-∞, Cmax, Ae (urine), Ae (feces); for ezetimibe, ezetimibe glucuronide and tacrolimus: AUC0-t, t½, tmax

Detailed description: Hypercholesterolemia is a frequent finding in organ transplant recipients receiving immunosuppressive drugs such as tacrolimus. To prevent increased cardiovascular morbidity and mortality in these patients, co-medication with lipid-lowering statins is recommended. However, treatment with statins is limited in many patients by insufficient cholesterol-lowering efficacy, drug interactions and serious adverse drug reactions (e. g. rhabdomyolysis). These patients may benefit from comedication with the cholesterol absorption inhibitor ezetimibe. Since tacrolimus and ezetimibe were shown to be substrates of the efflux transporter ABCB1 (P-glycoprotein), drug interactions between both compounds may occur. Therefore, this clinical study in healthy subjects was initiated to evaluate the clinical relevance of drug/drug interactions between tacrolimus and ezetimibe according to the accepted bioequivalence approach.

Minimum age: 18 Years. Maximum age: 45 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- age: 18 - 45 years

- sex: male and female

- ethnic origin: Caucasian

- body weight: 19 kg/m² to 27 kg/m²

- good health as evidenced by the results of the clinical examination, ECG, and the

laboratory check-up, which are judged by the clinical investigator not to differ in a clinical relevant way from the normal state

- written informed consent

Exclusion Criteria:

- known allergy to macrolide antibiotics

- existing cardiac or hematological diseases and/or pathological findings which might

interfere with safety, pharmacodynamic effect and/or pharmacokinetics of ezetimibe and sirolimus

- existing hepatic and renal diseases and/or pathological findings which might interfere

with safety, pharmacodynamic effect and/or pharmacokinetics of ezetimibe and sirolimus

- existing gastrointestinal diseases and/or pathological findings which might interfere

with safety, pharmacodynamic effect and/or pharmacokinetics of ezetimibe and sirolimus

- acute or chronic diseases which could affect drug absorption or metabolism

- history of any serious psychological disorder

- drug or alcohol dependence

- positive drug or alcohol screening

- smokers of 10 or more cigarettes per day

- positive screening results for HIV, HBV and HCV

- volunteers who are on a diet which could affect the pharmacokinetics of the drug

- heavy tea or coffee drinkers (more than 1L per day)

- lactation and pregnancy test positive or not performed

- volunteers suspected or known not to follow instructions

- volunteers who are unable to understand the written and verbal instructions, in

particular regarding the risks and inconveniences they will be exposed to as a result of their participation in the study

- volunteers liable to orthostatic dysregulation, fainting, or blackouts

- blood donation or other blood loss of more than 400 ml within the last 12 weeks prior

to the start of the study

- participation in a clinical trial during the last 3 months prior to the start of the

study

- less than 14 days after last acute disease

- any systemically available medication within 4 weeks prior to the intended first

administration unless, because of the terminal elimination half-life, complete elimination from the body can be assumed for the drug and/or its primary metabolites (except oral contraceptives)

- repeated use of drugs during the last 4 weeks prior to the intended first

administration, which can influence hepatic biotransformation (e. g. barbiturates, cimetidine, phenytoin, rifampicin)

- repeated use of drugs during the last 2 weeks prior to the intended first

administration which affect absorption (e. g. laxatives, metoclopramide, loperamide, antacids, H2-receptor antagonists)

- intake of grapefruit containing food or beverages within 7 days prior to

administration

- known allergic reactions to the active ingredients used or to constituents of the

pharmaceutical preparation

- subjects with severe allergies or multiple drug allergies

Department of Clinical Pharmacology, Greifswald 17487, Germany

Starting date: September 2007
Ending date: November 2007
Last updated: February 12, 2008